Substantial linkage disequilibrium across the insulin degrading enzyme locus but no association with late-onset Alzheimer's disease
Jones L., Abraham R., Myers A., DeVrieze FW., Hamshere MV., Thomas HM., Marshall H., Compton D., Spurlock G., Turic D., Hoogendorn B., Kwon JM., Petersen RC., Tanaglos E., Norton J., Morris JC., Bullock R., Liolitsa D., Lovestone S., Hardy J., Goate A., O'Donovan M., Williams J., Owen MJ.
Insulin degrading enzyme (IDE; insulysin; EC 184.108.40.206) is a 110 kDa neutral metallopeptidase which can degrade a number of peptides including b-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5′-flanking sequence of IDE using DHPLC and sequencing to detect sequence variants. We detected eight single nucleotide polymorphisms (SNPs), three in the 5′ flanking sequence and five in the coding sequence, of which three were found at < 5% frequency. None changed the amino acid sequence . We genotyped the five SNPs with allele frequencies of > 5% in 133 Caucasian late-onset AD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St Louis 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples nor with any haplotypes. Analysis of the marker D10S583 which maps 36kb upstream of IDE also failed to show association in 134 cases and 111 matched controls from the UK (P = 0.63). Strong LD was detected between the five SNPs which spanned the whole of the 120kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD, and therefore cannot account for the linkage between LOAD and 10q.